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The Journal of Neuroscience, August 3, 2005, 25(31):7111-7120; doi:10.1523/JNEUROSCI.1319-05.2005

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Neurobiology of Disease
Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

Yan Huang,¹ Erich E. Sirkowski,¹ John T. Stickney,² and Steven S. Scherer¹

¹Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, and ²Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. The C terminus of human Cx32 contains a putative prenylation motif that is conserved in Cx32 orthologs. Using [³H]mevalonolactone ([³H]MVA) incorporation, we demonstrated that wild-type human connexin32 can be prenylated in COS7 cells, in contrast to disease-associated mutations that are predicted to disrupt the prenylation motif. We generated transgenic mice that express these mutants in myelinating Schwann cells. Male mice expressing a transgene were crossed with female Gjb1-null mice; the male offspring were all Gjb1-null, and one-half were transgene positive; in these mice, all Cx32 was derived from expression of the transgene. The mutant human protein was properly localized in myelinating Schwann cells in multiple transgenic lines and did not alter the localization of other components of paranodes and incisures. Finally, both the C280G and the S281x mutants appeared to "rescue" the phenotype of Gjb1-null mice, because transgene-positive male mice had significantly fewer abnormally myelinated axons than did their transgene-negative male littermates. These results indicate that Cx32 is prenylated, but that prenylation is not required for proper trafficking of Cx32 and perhaps not even for certain aspects of its function, in myelinating Schwann cells.

Key words: X-linked Charcot-Marie-Tooth disease; CMT; neuropathy; myelin; Cx32; gap junction

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Received April 5, 2005; revised June 17, 2005; accepted June 18, 2005.

This article has been cited by other articles:

				I. Sargiannidou, N. Vavlitou, S. Aristodemou, A. Hadjisavvas, K. Kyriacou, S. S. Scherer, and K. A. Kleopa Connexin32 Mutations Cause Loss of Function in Schwann Cells and Oligodendrocytes Leading to PNS and CNS Myelination Defects J. Neurosci., April 15, 2009; 29(15): 4736 - 4749. [Abstract] [Full Text] [PDF]

				D. Locke, I. V. Koreen, and A. L. Harris Isoelectric points and post-translational modifications of connexin26 and connexin32 FASEB J, June 1, 2006; 20(8): 1221 - 1223. [Abstract] [Full Text] [PDF]

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